rs1991517 — TSHR Asp727Glu

TSHR Asp727Glu — How Your TSH Receptor Sensitivity Shapes Thyroid Function

The thyroid-stimulating hormone receptor (TSHR) sits on the surface of thyroid follicular cells, where it binds TSH from the pituitary and triggers the production of thyroid hormones T4 and T3. This receptor is a G-protein-coupled receptor¹¹ This receptor is a G-protein-coupled receptor
Activates both cAMP and phospholipase C pathways that controls virtually all aspects of thyroid function — hormone synthesis, thyroid cell growth, and iodine uptake. The Asp727Glu variant changes an aspartic acid to glutamic acid at position 727 in the intracellular tail of the receptor, altering its binding affinity to cyclic AMP²² altering its binding affinity to cyclic AMP
Computational modeling shows distinct binding energies: -7.27 vs -7.34 kcal/mol and thereby modulating signal transduction efficiency. This common polymorphism affects approximately 8-12% of people across populations³³ 8-12% of people across populations
Present in 0.6% as GG homozygotes in European populations and has emerged as a genetic factor influencing TSH levels, metabolic health, and thyroid disease risk.

The Mechanism

The wild-type Asp727 version of the TSHR maintains optimal signal transduction when TSH binds. The variant Glu727 substitution is conservative⁴⁴ The variant Glu727 substitution is conservative
Both aspartic acid and glutamic acid are negatively charged, but the single-carbon side chain difference alters the receptor's interaction with downstream signaling molecules, particularly cyclic AMP. When TSH binds to the receptor's extracellular domain, it triggers a conformational change that activates G proteins⁵⁵ it triggers a conformational change that activates G proteins
Gs protein activates adenylyl cyclase, producing cAMP on the intracellular side. The Glu727 variant appears to enhance this cAMP-mediated signaling pathway, making the receptor slightly more responsive to TSH stimulation. This increased sensitivity means that carriers require less circulating TSH⁶⁶ carriers require less circulating TSH
12.6% lower TSH levels in Glu727 carriers to achieve the same thyroid hormone output, effectively resetting the hypothalamic-pituitary-thyroid axis setpoint.

However, this enhanced receptor sensitivity has a paradoxical effect: in the developing thyroid gland, where proper TSH signaling is critical for differentiation and growth, the altered cAMP dynamics may impair normal thyroid development⁷⁷ impair normal thyroid development
Associated with 2.3-fold increased congenital hypothyroidism risk in GG homozygotes. The same variant that lowers TSH in healthy adults appears to increase vulnerability to thyroid dysgenesis or hypoplasia during fetal development.

The Evidence

The most comprehensive evidence for this variant's effects comes from a Danish twin study of 1,241 healthy adults⁸⁸ a Danish twin study of 1,241 healthy adults
Peeters et al. Eur J Endocrinol 2007, which found genotype frequencies of Asp/Asp 84.9%, Asp/Glu 14.5%, and Glu/Glu 0.6%. Carriers of the Glu727 allele (CG or GG genotypes) had significantly lower serum TSH levels⁹⁹ significantly lower serum TSH levels
1.60 ± 0.84 vs 1.78 ± 0.93 mU/L, P=0.04 compared to non-carriers, with regression analysis confirming the association (P=0.007). However, the polymorphism accounted for only 0.91% of total phenotypic variance in TSH levels and showed no association with thyroid size, thyroid hormones, or thyroid antibody levels¹⁰¹⁰ no association with thyroid size, thyroid hormones, or thyroid antibody levels
Suggesting specific effect on TSH regulation, indicating its influence is limited to the TSH feedback setpoint rather than broader thyroid function.

In the context of thyroid disease, a meta-analysis combining 1,044 congenital hypothyroidism cases and 1,649 controls¹¹¹¹ a meta-analysis combining 1,044 congenital hypothyroidism cases and 1,649 controls
Kollati et al. 3 Biotech 2020 found that the G-allele increased congenital hypothyroidism risk by 45%¹²¹² increased congenital hypothyroidism risk by 45%
OR: 1.45, 95% CI 1.20-1.76 in fixed-effect models, with the GG genotype showing a 2.3-fold increased risk¹³¹³ 2.3-fold increased risk
OR: 2.30, 95% CI 1.32-3.99. This association was consistent across seven published studies and is thought to reflect the variant's impact on cAMP-mediated thyroid development during gestation. Interestingly, early research into autoimmune thyroid diseases like Graves' disease initially examined rs1991517 but later excluded it¹⁴¹⁴ initially examined rs1991517 but later excluded it
Frequently present in healthy individuals, suggesting it is not a major driver of autoimmune thyroid pathology.

Beyond thyroid-specific effects, the variant has been linked to metabolic parameters. In a study of 349 nondiabetic elderly men¹⁵¹⁵ a study of 349 nondiabetic elderly men
Peeters et al. Clin Endocrinol 2007, carriers of the Glu727 allele showed significantly elevated markers of insulin resistance¹⁶¹⁶ significantly elevated markers of insulin resistance
Glucose (P=0.01), insulin (P=0.001), HbA1c (P=0.002), HOMA-IR (P=0.001), and leptin (P=0.008). The authors suggest this reflects direct TSH receptor activity in adipose tissue, where TSHR is expressed and may influence glucose metabolism independent of circulating thyroid hormone levels. Additionally, the Rotterdam Study found Glu727 carriers had 2.3% higher femoral neck bone mineral density¹⁷¹⁷ the Rotterdam Study found Glu727 carriers had 2.3% higher femoral neck bone mineral density
P=0.03, potentially mediated by the lower TSH levels, since TSH receptors are also expressed in bone.

Practical Implications

If you carry the Glu727 variant (CG or GG genotype), your baseline TSH levels may run lower than population averages while still being entirely normal for you. This has implications for thyroid function testing: what appears to be "low-normal" TSH (e.g., 0.8-1.5 mU/L) may be your optimal setpoint rather than a sign of subclinical hyperthyroidism. TSH levels vary significantly based on genetic factors¹⁸¹⁸ TSH levels vary significantly based on genetic factors
TSHR polymorphisms account for measurable variance in TSH setpoints, so individualized reference ranges are more meaningful than population-wide cutoffs.

For parents or prospective parents carrying the G-allele, awareness of the modest increase in congenital hypothyroidism risk may inform discussions about newborn screening. Standard newborn screening programs measure TSH at 4-5 days of life¹⁹¹⁹ Standard newborn screening programs measure TSH at 4-5 days of life
99% coverage in developed countries, so any thyroid dysgenesis would be caught early, but knowing the genetic predisposition reinforces the importance of ensuring screening is completed.

The metabolic associations—particularly insulin resistance in Glu727 carriers—suggest that maintaining metabolic health through lifestyle measures may be especially important. While the variant's effect size is modest, it adds to the cumulative genetic and environmental factors influencing glucose metabolism. Similarly, the higher bone mineral density in carriers is a protective factor, potentially offsetting other genetic or lifestyle-related osteoporosis risks.

Optimal thyroid function depends on adequate selenium and iodine intake²⁰²⁰ selenium and iodine intake
Selenium for deiodinase function, iodine as structural component of T4/T3. While the TSHR variant affects receptor sensitivity rather than thyroid hormone synthesis directly, ensuring micronutrient sufficiency supports overall thyroid axis function. Zinc also plays a role in TSH regulation²¹²¹ Zinc also plays a role in TSH regulation
Influences TSH release from pituitary and T4-to-T3 conversion, making it a relevant consideration for comprehensive thyroid support.

Interactions

The TSHR Asp727Glu variant interacts with polymorphisms in the DIO2 gene (particularly rs225014, Thr92Ala), which controls conversion of T4 to active T3 in peripheral tissues. A study of congenital hypothyroidism patients found concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism²²²² A study of congenital hypothyroidism patients found concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism
Combined effects are additive. Specifically, TSHR variants affect the production of T4 from the thyroid gland, while DIO2 variants affect local T3 production from circulating T4. Individuals with both TSHR Glu727 (lower TSH drive) and DIO2 Ala92 (reduced T4-to-T3 conversion) may experience a "double hit" scenario where both hormone production and peripheral activation are compromised, potentially requiring more careful thyroid hormone replacement strategies if hypothyroidism develops.

The variant's effect on TSH levels also influences the broader hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axis interaction. Stress and cortisol affect thyroid hormone secretion²³²³ Stress and cortisol affect thyroid hormone secretion
CRH and cortisol can suppress TSH and alter T4-to-T3 conversion, and individuals with genetically lower baseline TSH (like Glu727 carriers) may be more vulnerable to stress-induced thyroid dysfunction. Chronic stress leading to elevated cortisol can further suppress already-low TSH levels, potentially pushing carriers toward subclinical hypothyroidism.

The sleep-thyroid connection is another relevant interaction. TSH follows a circadian rhythm with natural elevation during early sleep²⁴²⁴ TSH follows a circadian rhythm with natural elevation during early sleep
Melatonin production signals nighttime thyroid adjustments, and disruption of sleep patterns (shift work, insomnia, sleep apnea) can dysregulate TSH secretion. Glu727 carriers with altered TSH setpoints may be particularly sensitive to circadian disruption, making consistent sleep-wake cycles especially important for maintaining stable thyroid function.